PHYSICAL SYMPTOMS AND THEIR MANAGEMENT
Great emphasis has been placed on addressing dying patients’ pain. In order to emphasize its importance, pain assessment has frequently been included as the fifth vital sign. Heightened consideration of pain has been advocated by large health care systems such as the Veterans’ Administration and accrediting bodies such as the Joint Commission on the Accreditation of Health Care Organizations (JCAHO). Although this embrace of pain has been symbolically important, available data suggests that making pain the fifth vital sign does not lead to improved pain management practices. In light of the growing opioid crisis in the United States, the emphasis on pain management has begun to be re-examined. For instance, in 2017 draft standards, the JCAHO recommends nonpharmacological pain treatment as well as identification of psychosocial risk factors for addiction. Importantly, good palliative care requires much more than good pain management. The frequency of symptoms varies by disease and other factors. The most common physical and psychological symptoms among all terminally ill patients include pain, fatigue, insomnia, anorexia, dyspnea, depression, anxiety, nausea, and vomiting. In the last days of life, terminal delirium is also common. Assessments of patients with advanced cancer have shown that patients experienced an average of 11.5 different physical and psychological symptoms (Table 9-4).
TABLE 9-4Common Physical and Psychological Symptoms of Terminally Ill Patients ||Download (.pdf) TABLE 9-4 Common Physical and Psychological Symptoms of Terminally Ill Patients
|Physical Symptoms ||Psychological Symptoms |
|Pain ||Anxiety |
|Fatigue and weakness ||Depression |
|Dyspnea ||Hopelessness |
|Insomnia ||Meaninglessness |
|Dry mouth ||Irritability |
|Anorexia ||Impaired concentration |
|Nausea and vomiting ||Confusion |
|Constipation ||Delirium |
|Cough ||Loss of libido |
|Swelling of arms or legs || |
|Itching || |
|Diarrhea || |
|Dysphagia || |
|Dizziness || |
|Fecal and urinary incontinence || |
|Numbness/tingling in hands/feet || |
In the vast majority of cases, evaluations to determine the etiology of these symptoms should be limited to the history and physical examination. In some cases, radiologic or other diagnostic examinations will provide sufficient benefit in directing optimal palliative care to warrant the risks, potential discomfort, and inconvenience, especially to a seriously ill patient. Only a few of the common symptoms that present difficult management issues will be addressed in this chapter. Additional information on the management of other symptoms, such as nausea and vomiting, insomnia, and diarrhea, can be found in Chaps. 41, 65, 27, and 42, respectively.
The frequency of pain among terminally ill patients varies significantly. Cancer (~85%), CHF (~75%), and AIDS have been associated with a higher prevalence of pain compared to other advanced illnesses, such as COPD (~45%), CKD (~40%), and dementia (~40%). One meta-analysis of adults with advanced or terminal illness found pain prevalence of 30–94% in patients with cancer, compared to 21–77% for COPD, 14–78% for CHF, 11–83% for ESRD, 14–63% for dementia, and 30–98% for AIDS.
There are two types of pain: nociceptive and neuropathic. Nociceptive pain is further divided into somatic or visceral pain. Somatic pain is the result of direct mechanical or chemical stimulation of nociceptors and normal neural signaling to the brain. It tends to be localized, aching, throbbing, and cramping. The classic example is bone metastases. Visceral pain is caused by nociceptors in gastrointestinal (GI), respiratory, and other organ systems. It is a deep or colicky type of pain classically associated with pancreatitis, myocardial infarction, or tumor invasion of viscera. Neuropathic pain arises from disordered nerve signals. It is described by patients as burning, electrical, or shock-like pain. Classic examples are post-stroke pain, tumor invasion of the brachial plexus, and herpetic neuralgia.
Pain is a subjective experience. Depending on the patient’s circumstances, perspective, and physiologic condition, the same physical lesion or disease state can produce different levels of reported pain and need for pain relief. Systematic assessment includes eliciting the following: (1) type: throbbing, cramping, burning, etc.; (2) periodicity: continuous, with or without exacerbations, or incident; (3) location; (4) intensity; (5) modifying factors; (6) effects of treatments; (7) functional impact; and (8) impact on patient. Several validated pain assessment measures may be used, including the Visual Analogue Scale (VAS), the Brief Pain Inventory (BPI), or the Numerical Pain Rating Scale (NRS-11). Other scales have been developed for neuropathic pain, such as the Neuropathic Pain Scale and the DN4 Questionnaire. Frequent reassessments on a consistent scale are essential to assess the impact of and need to readjust interventions.
Interventions for pain must be tailored to each individual, with the goal of preempting chronic pain and relieving breakthrough pain. At the end of life, there is rarely reason to doubt a patient’s report of pain. With the opioid crisis in the United States there is more emphasis on making opioids one component of multimodal analgesia. Nevertheless, at the end of life, pain medications, especially opioids, remain the cornerstone of management. If they are failing and nonpharmacologic interventions—including radiotherapy and anesthetic or neurosurgical procedures such as peripheral nerve blocks or epidural medications—are required, a pain consultation is appropriate.
Pharmacologic interventions still largely follow the World Health Organization three-step, “analgesic ladder” approach, which involves non-opioid analgesics, “mild” opioids, and “strong” opioids, with or without adjuvants (Chap. 10). Nonopioid analgesics, especially nonsteroidal anti-inflammatory drugs (NSAIDs), are the initial treatments for mild pain. They work primarily by inhibiting peripheral prostaglandins and reducing inflammation, but may also have central nervous system (CNS) effects. Additionally, NSAIDs have a ceiling effect. Ibuprofen, up to 2400 mg/d qid, has a minimal risk of causing bleeding and renal impairment and is a good initial choice. In patients with a history of severe GI or other bleeding, however, ibuprofen should be avoided. In patients with a history of mild gastritis or gastroesophageal reflux disease (GERD), acid-lowering therapy, such as a proton pump inhibitor, should be used. Acetaminophen is an alternative in patients with a history of GI bleeding and can be used safely at up to 4 g/d qid. In patients with liver dysfunction due to metastases or other causes, and in patients with heavy alcohol use, doses should be reduced.
If nonopioid analgesics are insufficient, opioids should be introduced. Opioids primarily work by interacting with μ opioid receptors to activate pain-inhibitory neurons in the CNS, although they also interact variably with δ and κ receptors. Receptor agonists, such as morphine, codeine, and fentanyl, produce analgesia by activating pain-inhibitory neurons in the CNS. Partial agonists, such as buprenorphine, have a ceiling effect for analgesia and a lower potential for abuse. They are useful for post-acute pain, but should not be used for chronic pain in end-of-life care. Pure antagonists, such as naloxone and methylnaltrexone, are used for reversal of opioid effects.
Traditionally, “weak” opioids such as codeine were used first. If they failed to relieve pain after dose escalation, “strong” opioids like morphine were used in doses of 5–10 mg every 4 h. However, this breakdown between “weak” and “strong” opioids is no longer commonly accepted, with smaller doses of “stronger” opioids frequently being preferred over similar or larger doses of “weaker” opioids, and different pain syndromes having different preferred therapies. Regardless, nonopioid analgesics should be combined with opioids, as they potentiate the effect of opioids.
For continuous pain, opioids should be administered on a regular, around-the-clock basis consistent with their duration of analgesia. They should not be provided only when the patient experiences pain; the goal is to prevent patients from experiencing pain. Patients should also be provided rescue medication, such as liquid morphine, for breakthrough pain, generally at 20% of the baseline dose. Patients should be informed that using the rescue medication does not obviate the need to take the next standard dose of pain medication. If the patient’s pain remains uncontrolled after 24 h and recurs before the next dose, requiring the patient to utilize the rescue medication, the daily opioid dose can be increased by the total dose of rescue medications used by the patient, or by 50% of the standing opioid daily dose for moderate pain and 100% for severe pain.
It is inappropriate to start with extended-release preparations. Instead, an initial focus on using short-acting preparations to determine how much is required in the first 24–48 h will allow clinicians to determine opioid needs. Once pain relief is obtained using short-acting preparations, the switch should be made to extended-release preparations. Even with a stable extended-release preparation regimen, the patient may experience incident pain, such as during movement or dressing changes. Short-acting preparations should be taken before such predictable episodes. Although less common, patients may have “end-of-dose failure” with long-acting opioids, meaning that they develop pain after 8 h in the case of an every-12-h medication. In these cases, a trial of giving an every-12-h medication every 8 h is appropriate.
Due to differences in opioid receptors, cross-tolerance among opioids is incomplete, and patients may experience different side effects with different opioids. Therefore, if a patient is not experiencing pain relief or is experiencing too many side effects, a change to another opioid preparation is appropriate. When switching, one should begin with 50–75% of the published equianalgesic dose of the new opioid.
Unlike NSAIDs, opioids have no ceiling effect; therefore, there is no maximum dose, no matter how many milligrams the patient is receiving. The appropriate dose is the dose needed to achieve pain relief. This is an important point for clinicians to explain to patients and families. Addiction or excessive respiratory depression is extremely unlikely in the terminally ill; fear of these side effects should neither prevent escalating opioid medications when the patient is experiencing insufficient pain relief, nor justify using opioid antagonists.
Opioid side effects should be anticipated and treated preemptively. Nearly all patients experience constipation that can be debilitating (see below). Failure to prevent constipation often results in noncompliance with opioid therapy. The preferred treatment is prevention. Cathartics (senna 2 tables qHS), stool softeners (docusate 100 mg PO qd), and/or laxatives (laxtulose 30 mL qd) are considered first-line. For refractory cases, opioid antagonists or other therapies, such as lubiprostone, should be considered.
Methylnaltrexone is the best-studied opioid antagonist for use in refractory opioid-induced constipation. It reverses opioid-induced constipation by blocking peripheral opioid receptors, but not central receptors, for analgesia. In placebo-controlled trials, it has been shown to cause laxation within 24 h of administration. As with the use of opioids, about a third of patients using methylnaltrexone experience nausea and vomiting, but unlike with opioid usage, tolerance usually develops within a week. Therefore, when one is beginning opioids, an antiemetic such as metoclopramide or a serotonin antagonist is often prescribed prophylactically and stopped after 1 week. Olanzapine has also been shown to have anti-nausea properties and can be effective in countering delirium or anxiety, with the advantage of some weight gain.
Drowsiness, a common side effect of opioids, also usually abates within a week. For refractory or severe cases, pharmacologic therapy should be considered. The best-studied agents are the psychostimulants dextroamphetamine, methylphenidate, and modafinil, although evidence regarding their efficacy is weak. Modafinil has the advantage of once-a-day dosing compared to methyphenidate’s twice daily dosing.
Seriously ill patients who require chronic pain relief rarely become addicted. Suspicion of addiction should not be a reason to withhold pain medications from terminally ill patients. Nonetheless, patients and families may withhold prescribed opioids for fear of addiction or dependence. Physicians and health care providers should reassure patients and families that the patient will not become addicted to opioids if they are used as prescribed for pain relief; this fear should not prevent the patient from taking the medications around the clock. However, diversion of drugs for use by other family members or illicit sale may occur. It may be necessary to advise the patient and caregiver about secure storage of opioids. Contract writing with the patient and family can help. If that fails, transfer to a safe facility may be necessary.
Tolerance describes the need to increase medication dosage for the same pain relief without a concurrent change in disease. In the case of patients with advanced disease, the need for increasing opioid dosage for pain relief usually is caused by disease progression rather than tolerance. Physical dependence is indicated by symptoms resulting from the abrupt withdrawal of opioids and should not be confused with addiction.
In recent years, the potential dangers of opioid drugs have become increasingly apparent. To help mitigate the risk of these powerful drugs, several strategies should be used to reduce the risk of aberrant drug use. To start, all patients should be assessed for their individual levels of risk. While there are multiple surveys available, including the Opioid Risk Tool, none have gained wide-spread use or validation. In general, however, it is important to screen for prior substance abuse and major psychiatric disorders.
For patients deemed to be high-risk, a multidisciplinary effort should be pursued to reduce the risk of adverse consequences, such as addiction and diversion. Prescribing strategies include selecting opioids with longer durations of action and lower street values, such as methadone, and prescribing smaller quantities with more frequent follow-up. Monitoring options include periodic urine screening and referral to pain specialists. In some cases, it may also be reasonable to consider not offering short-acting opioids for breakthrough pain. In no situation, however, should adequate pain-relief be withheld due to risk.
Adjuvant analgesic medications are nonopioids that potentiate the analgesic effects of opioids. They are especially important in the management of neuropathic pain. Gabapentin, an anticonvulsant initially studied in the setting of herpetic neuralgia, is now the first-line treatment for neuropathic pain resulting from a variety of causes. It is begun at 100–300 mg bid or tid, with 50–100% dose increments every 3 days. Usually 900–3600 mg/d in two or three doses is effective. The combination of gabapentin and nortriptyline may be more effective than gabapentin alone. One potential side effect of gabapentin to be aware of is confusion and drowsiness, especially in the elderly. Other effective adjuvant medications include pregabalin, which has the same mechanism of action as gabapentin, but is absorbed more efficiently from the GI tract. Lamotrigine is a novel agent whose mechanism of action is unknown, but has been shown to be effective. It is recommended to begin at 25–50 mg/d, increasing to 100 mg/d. Carbamazepine, a first-generation agent, has been proven effective in randomized trials for neuropathic pain. Other potentially effective anticonvulsant adjuvants include topiramate (25–50 mg qd or bid, rising to 100–300 mg/d) and oxcarbazepine (75–300 mg bid, rising to 1200 mg bid).
Glucocorticoids, preferably dexamethasone given once a day, can be useful in reducing inflammation that causes pain, while also elevating mood, energy, and appetite. Its main side effects include confusion, sleep difficulties, and fluid retention. Glucocorticoids are especially effective for bone pain and abdominal pain from distention of the GI tract or liver. Other drugs, including clonidine and baclofen, can be effective in providing pain relief. These drugs are adjuvants and generally should be used in conjunction with—not instead of—opioids. Methadone, carefully dosed because of its unpredictable half-life in many patients, has activity at the N-methyl-D-aspartamate (NMDA) receptor and is useful for complex pain syndromes and neuropathic pain. It is generally reserved for cases in which first-line opioids (morphine, oxycodone, hydromorphone) are either ineffective or unavailable.
Radiation therapy can treat bone pain from single metastatic lesions. Bone pain from multiple metastases can be amenable to radiopharmaceuticals such as strontium 89 and samarium 153. Bisphosphonates, such as pamidronate (90 mg every 4 weeks) and calcitonin (200 IU intranasally once or twice a day), also provide relief from bone pain, but have multi-day onsets of action.
Constipation is reported in up to 70–100% of patients requiring palliative care.
Although hypercalcemia and other factors can cause constipation, it is most frequently a predictable consequence of the use of opioids for pain and dyspnea relief, and of the anticholinergic effects of tricyclic anti-depressants, as well as due to the inactivity and poor diets common among seriously ill patients. If left untreated, constipation can cause substantial pain and vomiting, and also is associated with confusion and delirium. Whenever opioids and other medications known to cause constipation are used, preemptive treatment for constipation should be instituted.
Assessing constipation can be difficult, because people describe it differently. Four commonly used assessment scales are the Bristol Stool Form Scale, the Constipation Assessment Scale, the Constipation Visual Analogue Scale, and the Eton Scale Risk Assessment for Constipation. The Bowel Function Index can be used to quantify opioid induced constipation. The physician should establish the patient’s previous bowel habits, as well as any changes in subjective and objective qualities such as bloating or decreased frequency. Abdominal and rectal examinations should be performed to exclude impaction or an acute abdomen. Radiographic assessments beyond a simple flat plate of the abdomen in cases in which obstruction is suspected are rarely necessary.
Any measure to address constipation during end-of-life care should include interventions to reestablish comfortable bowel habits and to relieve pain or discomfort. Although physical activity, adequate hydration, and dietary treatments with fiber can be helpful, each is limited in its effectiveness for most seriously ill patients, and fiber may exacerbate problems in the setting of dehydration or if impaired motility is the etiology. Fiber is contraindicated in the presence of opioid use. Stimulant and osmotic laxatives, stool softeners, fluids, and enemas are the mainstays of therapy (Table 9-5). To prevent constipation from opioids and other medications, a combination of a laxative and a stool softener (such as senna and docusate) should be used. If after several days of treatment a bowel movement has not occurred, a rectal examination to remove impacted stool and place a suppository is necessary. For patients with impending bowel obstruction or gastric stasis, octreotide to reduce secretions can be helpful. For patients in whom the suspected mechanism is dysmotility, metoclopramide can be helpful.
TABLE 9-5Medications for the Management of Constipation ||Download (.pdf) TABLE 9-5 Medications for the Management of Constipation
|Intervention ||Dose ||Comment |
|Stimulant laxatives || ||These agents directly stimulate peristalsis and may reduce colonic absorption of water. |
| Prune juice ||120–240 mL/d ||Work in 6–12 h. |
| Senna (Senokot) ||2–8 tablets PO bid || |
| Bisacodyl ||5–15 mg/d PO, PR || |
|Osmotic laxatives || ||These agents are not absorbed. They attract and retain water in the gastrointestinal tract. |
| Lactulose ||15–30 mL PO q4–8h ||Lactulose may cause flatulence and bloating. |
| Magnesium hydroxide (Milk of Magnesia) ||15–30 mL/d PO ||Lactulose works in 1 day, magnesium products in 6 h. |
| Magnesium citrate ||125–250 mL/d PO || |
|Stool softeners || ||These agents work by increasing water secretion and as detergents, increasing water penetration into the stool. |
| Sodium docusate (Colace) ||300–600 mg/d PO ||Work in 1–3 days. |
| Calcium docusate ||300–600 mg/d PO || |
|Suppositories and enemas || || |
| Bisacodyl ||10–15 PR qd || |
| Sodium phosphate enema ||PR qd ||Fixed dose, 4.5 oz, Fleet’s. |
Up to 70% of patients with advanced cancer have nausea, defined as the subjective sensation of wanting to vomit.
Nausea and vomiting are both caused by stimulation at one of four sites: the GI tract, the vestibular system, the chemoreceptor trigger zone (CTZ), and the cerebral cortex. Medical treatments for nausea are aimed at receptors at each of these sites: The GI tract contains mechanoreceptors, chemoreceptors, and 5-hydroxytryptamine type 3 (5-HT3) receptors; the vestibular system probably contains histamine and acetylcholine receptors; and the CTZ contains chemoreceptors, dopamine type 2 receptors, and 5-HT3 receptors. An example of nausea that most likely is mediated by the cortex is anticipatory nausea before a dose of chemotherapy or other noxious stimuli.
Specific causes of nausea include metabolic changes (liver failure, uremia from renal failure, hypercalcemia), bowel obstruction, constipation, infection, GERD, vestibular disease, brain metastases, medications (including antibiotics, NSAIDs, proton pump inhibitors, opioids, and chemotherapy), and radiation therapy. Anxiety can also contribute to nausea.
Medical treatment of nausea is directed at the anatomic and receptor-mediated cause revealed by a careful history and physical examination. When no specific cause of nausea is identified, many advocate beginning treatment with either metoclopramide, a serotonin type 3 (5-HT3) receptor antagonist like ondansetron, granisetron, palonosetron, dolasetron, tropisetron, or ramosetron, or a dopamine antagonist such as chlorpromazine, haloperidol or prochlorperazine. When decreased motility is suspected, metoclopramide can be an effective treatment. When inflammation of the GI tract is suspected, glucocorticoids, such as dexamethasone, are an appropriate treatment. For nausea that follows chemotherapy and radiation therapy, one of the 5-HT3 receptor antagonists or neurokinin-1 antagonists, such as aprepitant or fosaprepitant, is recommended. Clinicians should attempt prevention of post-chemotherapy nausea, rather than simply providing treatment after the fact. Current clinical guidelines recommend tailoring the strength of treatments to the specific emetic risk posed by a specific chemotherapy drug. When a vestibular cause (such as “motion sickness” or labyrinthitis) is suspected, antihistamines, such as meclizine (whose primary side effect is drowsiness), or anticholinergics, such as scopolamine, can be effective. In anticipatory nausea, patients can benefit from non-pharmacological interventions, such as biofeedback and hypnosis. The most common pharmacological intervention for anticipatory nausea is a benzodiazepine, such as lorazepam. As with antihistamines, drowsiness and confusion are the main side effects.
The use of medical marijuana or oral cannabinoids for palliative treatment of nausea is controversial, as there are no controlled trials showing its effectiveness for patients at the end of life. A 2015 meta-analysis showed “low-quality evidence suggesting that cannabinoids were associated with improvements in nausea and vomiting due to chemotherapy,” and such treatments are not as good as 5-HT3 receptor antagonists and can sometimes even cause cannabis hyperemesis syndrome. Older patients—the vast majority of dying patients— seem to tolerate cannabinoids poorly.
Dyspnea is the subjective experience of being short of breath. Over 50%, and as many as 75%, of dying patients, especially those with lung cancer, congestive heart failure and COPD, experience dyspnea at some point near the end of life. Dyspnea is among the most distressing of physical symptoms and can be even more distressing than pain.
As with pain, dyspnea is a subjective experience that may not correlate with objective measures of PO2, PCO2, or respiratory rate. Consequently, measurements of oxygen saturation through pulse oximetry or blood gases are rarely helpful in guiding therapy. Despite the limitations of existing assessment methods, physicians should regularly assess and document patients’ experience of dyspnea and its intensity. Guidelines recommend visual analogue dyspnea scales to assess the severity of symptoms and the effects of treatment. Potentially reversible or treatable causes of dyspnea include infection, pleural effusions, pulmonary emboli, pulmonary edema, asthma, and tumor encroachment on the airway. However, the risk-versus-benefit ratio of the diagnostic and therapeutic interventions for patients with little time left to live must be considered carefully before undertaking diagnostic steps. Frequently, the specific etiology cannot be identified, and dyspnea is the consequence of progression of the underlying disease that cannot be treated. The anxiety caused by dyspnea and the choking sensation can significantly exacerbate the underlying dyspnea in a negatively reinforcing cycle.
When reversible or treatable etiologies are diagnosed, they should be treated as long as the side effects of treatment, such as repeated drainage of effusions or anticoagulants, are less burdensome than the dyspnea itself. More aggressive treatments such as stenting a bronchial lesion may be warranted if it is clear that the dyspnea is due to tumor invasion at that site and if the patient and family understand the risks of such a procedure.
Usually, treatment will be symptomatic (Table 9-6). Supplemental oxygen does not appear to be effective. “A systematic review of the literature failed to demonstrate a consistent beneficial effect of oxygen inhalation over air inhalation for study participants with dyspnea due to end-stage cancer or cardiac failure.” Therefore, oxygen may be no more than an expensive placebo. Low-dose opioids reduce the sensitivity of the central respiratory center and relieve the sensation of dyspnea. If patients are not receiving opioids, weak opioids can be initiated; if patients are already receiving opioids, morphine or other stronger opioids should be used. Controlled trials do not support the use of nebulized opioids for dyspnea at the end of life. Phenothiazines and chlorpromazine may be helpful when combined with opioids. Benzodiazepines can be helpful in treating dyspnea, but only if anxiety is present. Benzodiazepines should neither be used as first-line therapy nor if there is no anxiety. If the patient has a history of COPD or asthma, inhaled bronchodilators and glucocorticoids may be helpful. If the patient has pulmonary edema due to heart failure, diuresis with a medication such as furosemide is indicated. Excess secretions can be transdermally or intravenously dried with scopolamine. More general interventions that medical staff can perform include sitting the patient upright, removing smoke or other irritants like perfume, ensuring a supply of fresh air with sufficient humidity, and minimizing other factors that can increase anxiety.
TABLE 9-6Medications for the Management of Dyspnea ||Download (.pdf) TABLE 9-6 Medications for the Management of Dyspnea
|Intervention ||Dose ||Comments |
|Weak opioids || ||For patients with mild dyspnea |
| Codeine (or codeine with 325 mg acetaminophen) ||30 mg PO q4h ||For opioid-naïve patients |
| Hydrocodone ||5 mg PO q4h || |
|Strong opioids || ||For opioid-naïve patients with moderate to severe dyspnea |
| Morphine ||5–10 mg PO q4h ||For patients already taking opioids for pain or other symptoms |
| ||30–50% of baseline opioid dose q4h || |
| Oxycodone ||5–10 mg PO q4h || |
| Hydromorphone ||1–2 mg PO q4h || |
|Anxiolytics || ||Give a dose every hour until the patient is relaxed, then provide a dose for maintenance |
| Lorazepam ||0.5–2.0 mg PO/SL/IV qh then q4–6h || |
| Clonazepam ||0.25–2.0 mg PO q12h || |
| Midazolam ||0.5 mg IV q15min || |
Fatigue is one of the most commonly reported symptoms of not only cancer treatment, but also of the palliative care of multiple sclerosis, COPD, heart failure, and HIV. More than 90% of terminally ill patients experience fatigue and/or weakness. Fatigue is frequently cited among the most distressing symptoms.
The multiple causes of fatigue in the terminally ill can be categorized as resulting from the underlying disease; from disease-induced factors such as tumor necrosis factor and other cytokines; and from secondary factors such as dehydration, anemia, infection, hypothyroidism, and drug side effects. In addition to low caloric intake, loss of muscle mass and changes in muscle enzymes may play an important role in fatigue during terminal illness. The importance of changes in the CNS, especially the reticular activating system, have been hypothesized based on reports of fatigue in patients receiving cranial radiation, experiencing depression, or having chronic pain in the absence of cachexia or other physiologic changes. Finally, depression and other causes of psychological distress can contribute to fatigue.
Like pain and dyspnea, fatigue is subjective, as it represents a patient’s sense of tiredness and decreased capacity for physical work. Objective changes, even in body mass, may be absent. Consequently, assessment must rely on patient self-reporting. Scales used to measure fatigue, such as the Edmonton Functional Assessment Tool, the Fatigue Self-Report Scales, and the Rhoten Fatigue Scale, are usually appropriate for research, but not clinical purposes. In clinical practice, a simple performance assessment such as the Karnofsky Performance Status or the Eastern Cooperative Oncology Group’s question “How much of the day does the patient spend in bed?” may be the best measure. In this 0–4 performance status assessment, 0 = normal activity; 1 = symptomatic without being bedridden; 2 = requiring some, but <50%, bed time; 3 = bedbound more than half the day; and 4 = bedbound all the time. Such a scale allows for assessment over time and correlates with overall disease severity and prognosis. A 2008 review by the European Association of Palliative Care also described several longer assessment tools that contained 9–20 items, including the Piper Fatigue Inventory, the Multidimensional Fatigue Inventory, and the Brief Fatigue Inventory (BFI).
Reversible causes of fatigue, such as anemia and infection, should be treated. However, at the end of life, it must be realistically acknowledged that fatigue will not be “cured.” The goal is to ameliorate fatigue and help patients and families adjust expectations. Behavioral interventions should be utilized to avoid blaming the patient for inactivity and to educate both the family and the patient that the underlying disease causes physiologic changes that produce low energy levels. Understanding that the problem is physiologic and not psychological can help alter expectations regarding the patient’s level of physical activity. Practically, this may mean reducing routine activities such as housework, cooking, and social events outside the house, and making it acceptable to receive guests while lying on a couch. At the same time, the implementation of exercise regimens and physical therapy can raise endorphins, reduce muscle wasting, and decrease the risk of depression. In addition, ensuring good hydration without worsening edema may help reduce fatigue. Discontinuing medications that worsen fatigue may help, including cardiac medications, benzodiazepines, certain antidepressants, or opioids if the pain is well-controlled. As end-of-life care proceeds into its final stages, fatigue may protect patients from further suffering, and continued treatment could be detrimental.
Only a few pharmacologic interventions target fatigue and weakness. Randomized controlled trials suggest glucocorticoids can increase energy and enhance mood. Dexamethasone (8 mg per d) is preferred for its once-a-day dosing and minimal mineralocorticoid activity. Benefit, if any, is usually seen within the first month. For fatigue related to anorexia, megestrol (480–800 mg) can be helpful. Psychostimulants such as dextroamphetamine (5–10 mg PO) and methylphenidate (2.5–5 mg PO) may enhance energy levels, although controlled trials have not shown these drugs to be effective for fatigue induced by mild to moderate cancer. Doses should be given in the morning and at noon to minimize the risk of counterproductive insomnia. Modafinil and armodafinil, developed for narcolepsy, have shown promise in the treatment of fatigue and have the advantage of once-daily dosing. Their precise role in fatigue at the end of life has not been documented, but may be worth trying if other interventions are not beneficial. Anecdotal evidence suggests that L-carnitine may improve fatigue, depression, and sleep disruption.
When patients experience severe symptoms, such as pain or dyspnea, that cannot be relieved by conventional interventions or experience acute catastrophic symptoms, such as uncontrolled seizures, then palliative sedation should be considered as an intervention of last resort. Palliative sedation is used in distressing situations that cannot be addressed in other ways. It can be abused if done to hasten death (which it usually does not), when at the request of the family, rather than the patient’s wishes, or when there are other interventions that could still be tried. The use of palliative sedation in cases of extreme existential or spiritual distress remains controversial. Typically, palliative sedation should be introduced only after the patient and family have been assured that all other interventions have been tried, and after the patient and their loved ones have been able to “say goodbye.”
Palliative sedation can be achieved by significantly increasing opioid doses until patients become unconscious, then putting them on a continuous infusion. Another commonly used medication for palliative sedation is midazolam at 1–5 mg IV every 5–15 min to calm the patient, followed by a continuous IV or subcutaneous infusion of 1 mg per h. In hospital settings, a continuous propofol infusion of 5 μg/kg per min can be used. There are also other, less commonly used medications for palliative sedation that include levomepromazine, chlorpromazine, and phenobarbital.
PSYCHOLOGICAL SYMPTOMS AND THEIR MANAGEMENT
Depression at the end of life presents an apparently paradoxical situation. Many people believe that depression is normal among seriously ill patients, because they are dying. People frequently say, “Wouldn’t you be depressed?” Although sadness, anxiety, anger, and irritability are normal responses to a serious condition, they are typically of modest intensity and transient. Persistent sadness and anxiety and the physically disabling symptoms that they can lead to are abnormal and suggestive of major depression. The precise number of terminally ill patients who are depressed is uncertain, primarily due to a lack of consistent diagnostic criteria and screening. Careful follow-up of patients suggests that while as many as 75% of terminally ill patients experience depressive symptoms, ~25% of terminally ill patients have major depression. Depression at the end of life is concerning, because it can decrease the quality of life, interfere with closure in relationships and other separation work, obstruct adherence to medical interventions, and amplify the suffering associated with pain and other symptoms.
Previous history of depression, family history of depression or bipolar disorder, and prior suicide attempts are associated with increased risk for depression among terminally ill patients. Other symptoms, such as pain and fatigue, are associated with higher rates of depression; uncontrolled pain can exacerbate depression, and depression can cause patients to be more distressed by pain. Many medications used in the terminal stages, including glucocorticoids, and some anticancer agents, such as tamoxifen, interleukin 2, interferon α, and vincristine, also are associated with depression. Some terminal conditions, such as pancreatic cancer, certain strokes, and heart failure, have been reported to be associated with higher rates of depression, although this is controversial. Finally, depression may be attributable to grief over the loss of a role or function, social isolation, or loneliness.
Unfortunately, most studies suggest that depressed patients at the end of life are neither diagnosed, nor even properly treated if diagnosed. Diagnosing depression among seriously ill patients is complicated, as many of the vegetative symptoms in the DSM-V (Diagnostic and Statistical Manual of Mental Disorders) criteria for clinical depression—insomnia, anorexia and weight loss, fatigue, decreased libido, and difficulty concentrating—are associated with the process of dying itself. The assessment of depression in seriously ill patients therefore should focus on the dysphoric mood, helplessness, hopelessness, and lack of interest, enjoyment, and concentration in normal activities. It is now recommended that patients near the end of life should be screened either with the Patient Health Questionnarie-9 (PHQ-9) or the PHQ-2 which asks “Over the past two weeks, how often have you been bothered by any of the following problems? (1) Little interest or pleasure in doing things and (2) feeling down, depressed or hopeless.” The answer categories are: Not at all, Several days, More than half the days, Nearly every day. There are other possible diagnostic tools such as the short form of the Beck Depression Index or a visual analog scale.
Certain conditions may be confused with depression. Endocrinopathies, such as hypothyroidism and Cushing’s syndrome, electrolyte abnormalities, such as hypercalcemia, and akathisia, especially from dopamine-blocking antiemetics such as metoclopramide and prochlorperazine, can mimic depression and should be excluded.
Under-treatment of depressed, terminally ill patients is common. Physicians must treat any physical symptom, such as pain, that may be causing or exacerbating depression. Fostering adaptation to the many losses that the patient is experiencing can also be helpful. Unfortunately, there are few randomized trials to guide such interventions. Thus, treatment typically follows the treatment used for non-terminally ill depressed patients.
While there are no randomized controlled trials, nonpharmacologic interventions, including group or individual psychological counseling, and behavioral therapies such as relaxation and imagery can be helpful, especially in combination with drug therapy.
Pharmacologic interventions remain at the core of therapy. The same medications are used to treat depression in terminally ill as in non-terminally ill patients. Psychostimulants may be preferred for patients with a poor prognosis, or for those with fatigue or opioid-induced somnolence. Psychostimulants are comparatively fast-acting, working within a few days instead of the weeks required for selective serotonin reuptake inhibitors (SSRIs). Dextroamphetamine or methylphenidate should be started at 2.5–5.0 mg in the morning and at noon, the same starting doses used for treating fatigue. The doses can eventually be escalated up to 15 mg bid. Modafinil is started at 100 mg qd and can be increased to 200 mg if there is no effect at the lower dose. Pemoline is a nonamphetamine psychostimulant with minimal abuse potential. It is also effective as an antidepressant beginning at 18.75 mg in the morning and at noon. Because it can be absorbed through the buccal mucosa, it is preferred for patients with intestinal obstruction or dysphagia. If it is used for prolonged periods, liver function must be monitored. The psychostimulants can also be combined with more traditional antidepressants while waiting for the antidepressants to become effective, then tapered down after a few weeks if necessary. Psychostimulants have side effects, particularly initial anxiety, insomnia, and very rarely paranoia, which may necessitate lowering the dose or discontinuing treatment.
Mirtazapine, an antagonist at the postsynaptic serotonin receptors, is a promising psychostimulant. It should be started at 7.5 mg before bed and titrated up no more than once every 1–2 weeks to a maximal dose of 45 mg per d. It has sedating, antiemetic, and anxiolytic properties, with few drug interactions. Its side effect of weight gain may be beneficial for seriously ill patients; it is available in orally disintegrating tablets.
For patients with a prognosis of several months or longer, SSRIs, including fluoxetine, sertraline, paroxetine, escitalopram, and citalopram, and serotonin-noradrenaline reuptake inhibitors, such as venlafaxine and duloxetine, are the preferred treatments, due to their efficacy and comparatively few side effects. Because low doses of these medications may be effective for seriously ill patients, one should use half the usual starting dose as for healthy adults. The starting dose for fluoxetine is 10 mg once a day. In most cases, once-a-day dosing is possible. The choice of which SSRI to use should be driven by (1) the patient’s past success or failure with the specific medication and (2) the most favorable side-effect profile for that specific agent. For instance, for a patient in whom fatigue is a major symptom, a more activating SSRI (fluoxetine) would be appropriate. For a patient in whom anxiety and sleeplessness are major symptoms, a more sedating SSRI (paroxetine) would be appropriate. Importantly, it can take up to 4 weeks for these drugs to have an effect.
Atypical antidepressants are recommended only in select circumstances, usually with the assistance of a specialty consultation. Trazodone can be an effective antidepressant, but is sedating and can cause orthostatic hypotension and, occasionally, priapism. Therefore, it should be used before bed and only when a sedating effect is desired, and is often used for patients with insomnia, at a dose starting at 25 mg. Bupropion can also be used. In addition to its antidepressant effects, bupropion is energizing, making it useful for depressed patients who experience fatigue. However, it can cause seizures, preventing its use for patients with a risk of CNS neoplasms or terminal delirium. Finally, alprazolam, a benzodiazepine, starting at 0.25–1.0 mg tid, can be effective in seriously ill patients who have a combination of anxiety and depression. Although it is potent and works quickly, it has many drug interactions and may cause delirium, especially among very ill patients, because of its strong binding to the benzodiazepine–γ-aminobutyric acid (GABA) receptor complex.
Unless used as adjuvants for the treatment of pain, tricyclic antidepressants are not recommended. While they can be effective, their therapeutic window and serious side effects typically limit their utility. Similarly, monoamine oxidase (MAO) inhibitors are not recommended because of their side effects and dangerous drug interactions.
In the weeks or months before death, delirium is uncommon, although it may be significantly underdiagnosed. However, delirium becomes relatively common in the days and hours immediately before death. Up to 85% of patients dying from cancer may experience terminal delirium.
Delirium is a global cerebral dysfunction characterized by alterations in cognition and consciousness. It is frequently preceded by anxiety, changes in sleep patterns (especially reversal of day and night), and decreased attention. In contrast to dementia, delirium has an acute onset, is characterized by fluctuating consciousness and inattention, and is reversible, although reversibility may be more theoretical than real for patients near death. Delirium may occur in a patient with dementia; indeed, patients with dementia are more vulnerable to delirium.
Causes of delirium include metabolic encephalopathy arising from liver or renal failure, hypoxemia, or infection; electrolyte imbalances such as hypercalcemia; paraneoplastic syndromes; dehydration; and primary brain tumors, brain metastases, or leptomeningeal spread of tumor. Among dying patients, delirium is commonly caused by side effects of treatments, including radiation for brain metastases and medications, such as opioids, glucocorticoids, anticholinergic drugs, antihistamines, antiemetics, benzodiazepines, and chemotherapeutic agents. The etiology may be multifactorial; e.g., dehydration may exacerbate opioid-induced delirium.
Delirium should be recognized in any terminally ill patient exhibiting new onset of disorientation, impaired cognition, somnolence, fluctuating levels of consciousness, or delusions with or without agitation. Delirium must be distinguished from acute anxiety, depression, and dementia. The central distinguishing feature is altered consciousness, which usually is not noted in anxiety, depression, or dementia. Although “hyperactive” delirium, characterized by overt confusion and agitation, is probably more common, patients should also be assessed for “hypoactive” delirium, which is characterized by sleep-wake reversal and decreased alertness.
In some cases, use of formal assessment tools such as the Mini-Mental Status Examination (which does not distinguish delirium from dementia) and the Delirium Rating Scale (which does distinguish delirium from dementia) may be helpful in distinguishing delirium from other processes. The patient’s list of medications must be evaluated carefully. Nonetheless, a reversible etiologic factor for delirium is found in fewer than half of all terminally ill patients. Given that most terminally ill patients experiencing delirium are very close to death and often at home, extensive diagnostic evaluations such as lumbar punctures and neuroradiologic examinations are inappropriate.
One of the most important objectives of terminal care is to provide terminally ill patients the lucidity to say goodbye to the people they love. Delirium, especially when in combination with agitation during the final days, is distressing to family and caregivers. A strong determinant of bereavement difficulties is witnessing a difficult death. Thus, terminal delirium should be treated aggressively.
At the first sign of delirium, such as day-night reversal with slight changes in mentation, the physician should let the family members know that it is time to be sure that everything they want to say has been said. The family should be informed that delirium is common just before death.
If medications are suspected of being a cause of the delirium, unnecessary agents should be discontinued. Other potentially reversible causes, such as constipation, urinary retention, and metabolic abnormalities, should be treated. Supportive measures aimed at providing a familiar environment should be instituted, including restricting visits only to individuals with whom the patient is familiar and eliminating new experiences; orienting the patient, if possible, by providing a clock and calendar; and gently correcting the patient’s hallucinations or cognitive mistakes.
Pharmacologic management focuses on the use of neuroleptics and, in extreme cases, anesthetics (Table 9-7). Haloperidol remains the first-line therapy. Usually, patients can be controlled with a low dose (1–3 mg/d), given every 6 h, although some may require as much as 20 mg/d. Haloperidol can be administered PO, SC, or IV. IM injections should not be used, except when this is the only way to address a patient’s delirium. Olanzapine, an atypical neuroleptic, has shown significant effectiveness in completely resolving delirium in cancer patients. It also has other beneficial effects for terminally ill patients, including anti-nausea, antianxiety, and weight gain. Olanzapine is useful for patients with longer anticipated life expectancies, because it is less likely to cause dysphoria and has a lower risk of dystonic reactions. Additionally, because olanzapine is metabolized through multiple pathways, it can be used in patients with hepatic and renal dysfunction. Olanzapine has the disadvantage that it is only available orally and takes a week to reach steady state. The usual dose is 2.5–5 mg PO bid. Chlorpromazine (10–25 mg every 4–6 h) can be useful if sedation is desired and can be administered IV or PR in addition to PO. Dystonic reactions resulting from dopamine blockade are a side effect of neuroleptics, although they are reported to be rare when these drugs are used to treat terminal delirium. If patients develop dystonic reactions, benztropine should be administered. Neuroleptics may be combined with lorazepam to reduce agitation when the delirium is the result of alcohol or sedative withdrawal.
TABLE 9-7Medications for the Management of Delirium
If no response to first-line therapy is observed, a specialty consultation should be obtained with a goal to change to a different medication. If the patient fails to improve after a second neuroleptic, sedation with either an anesthetic such as propofol or continuous-infusion midazolam may be necessary. By some estimates, as many as 25% of patients at the very end of life who experience delirium, especially restless delirium with myoclonus or convulsions, may require sedation.
Physical restraints should be used with great reluctance and only when the patient’s violence is threatening to himself or others. If restraints are used, their appropriateness should be frequently reevaluated.
Sleep disorders, defined as difficulty initiating sleep or maintaining sleep, sleep difficulty at least 3 nights a week, or sleep difficulty that causes impairment of daytime functioning, occurs in 19–63% of patients with advanced cancer. Some 30–74% of patients with other end-stage conditions, including AIDS, heart disease, COPD, and renal disease, experience insomnia.
Patients with cancer may experience changes in sleep efficiency, such as an increase in stage I sleep. Insomnia may also coexist with both physical illnesses, like thyroid disease, and psychological illnesses, like depression and anxiety. Medications, including antidepressants, psychostimulants, steroids, and β agonists, are significant contributors to sleep disorders, as are caffeine and alcohol. Multiple over-the-counter medications contain caffeine and antihistamines, which can contribute to sleep disorders.
Assessments should include specific questions concerning sleep onset, sleep maintenance, and early-morning wakening, as these will provide clues to both the causative agents and management of insomnia. Patients should be asked about previous sleep problems, screened for depression and anxiety, and asked about symptoms of thyroid disease. Caffeine and alcohol are prominent causes of sleep problems, and a careful history of the use of these substances should be obtained. Both excessive use and withdrawal from alcohol can be causes of sleep problems.
The mainstays of any intervention include improvement of sleep hygiene (encouragement of regular time for sleep, decreased nighttime distractions, elimination of caffeine and other stimulants and alcohol), interventions to treat anxiety and depression, and treatment for the insomnia itself. For patients with depression who have insomnia and anxiety, a sedating antidepressant such as mirtazapine can be helpful. In the elderly, trazodone, beginning at 25 mg at nighttime, is an effective sleep aid at doses lower than those which cause its antidepressant effect. Zolpidem may have a decreased incidence of delirium in patients compared with traditional benzodiazepines, but this has not been clearly established. When benzodiazepines are prescribed, short-acting ones (such as lorazepam) are favored over longer-acting ones (such as diazepam). Patients who receive these medications should be observed for signs of increased confusion and delirium.
SOCIAL NEEDS AND THEIR MANAGEMENT
Dying can impose substantial economic strains on patients and families, potentially causing distress. In the United States, which has one of the least comprehensive health insurance systems among developed countries, a quarter of families coping with end-stage cancer report that care was a major financial burden and a third used up most of their savings. Among Medicare beneficiaries, average out-of-pocket costs were >$8,000. Between 10 and 30% of families are forced to sell assets, use savings, or take out a mortgage to pay for the patient’s health care costs.
The patient is likely to reduce hours worked, and eventually stop working altogether. In 20% of cases, a family member of the terminally ill patient also must stop working to provide care. The major underlying causes of economic burden are related to poor physical functioning and care needs, such as the need for housekeeping, nursing, and personal care. More debilitated patients and poor patients experience greater economic burdens.
The economic burden of end-of-life care should not be ignored as a private matter. It has been associated with a number of adverse health outcomes, including preferring comfort care over life-prolonging care, as well as consideration of euthanasia or physician-assisted suicide (PAS). Economic burdens increase the psychological distress of the families and caregivers of terminally ill patients, and poverty is associated with many adverse health outcomes. Importantly, recent studies have found that “patients with advanced cancer who reported having end-of-life conversations with physicians had significantly lower health care costs in their final week of life. Higher costs were associated with worse quality of death.” Assistance from a social worker, early on if possible, to ensure access to all available benefits may be helpful. Many patients, families, and health care providers are unaware of options for long-term care insurance, respite care, the Family Medical Leave Act (FMLA), and other sources of assistance. Some of these options (such as respite care) may be part of a formal hospice program, but others (such as the FMLA) do not require enrollment in a hospice program.
Settling personal issues and closing the narrative of lived relationships are universal needs. When asked if sudden death or death after an illness is preferable, respondents often initially select the former, but soon change to the latter as they reflect on the importance of saying goodbye. Bereaved family members who have not had the chance to say goodbye often have a more difficult grief process.
Care of seriously ill patients requires efforts to facilitate the types of encounters and time spent with family and friends that are necessary to meet those needs. Family and close friends may need to be accommodated in hospitals and other facilities with unrestricted visiting hours, which may include sleeping near the patient, even in otherwise regimented institutional settings. Physicians and other health care providers may be able to facilitate and resolve strained interactions between the patient and other family members. Assistance for patients and family members who are unsure about how to create or help preserve memories, whether by providing materials such as a scrapbook or memory box, or by offering them suggestions and informational resources, can be deeply appreciated. Taking photographs and creating videos can be especially helpful to terminally ill patients who have younger children or grandchildren.
Caring for seriously ill patients places a heavy burden on families. Families are frequently required to provide transportation and homemaking, as well as other services. Typically, paid professionals, such as home health nurses and hospice workers, supplement family care; only about a quarter of all caregiving consists of exclusively paid professional assistance. Over the last 40 years, there has been a significant decline in the United States of deaths occurring in hospitals, with a simultaneous increase in deaths in other facilities and at home. Over a third of deaths occur in patients’ home. This increase in out-of-hospital deaths increases reliance on families for end-of-life care. Increasingly, family members are being called upon to provide physical care (such as moving and bathing patients) and medical care (such as assessing symptoms and giving medications) in addition to emotional care and support.
Three-quarters of family caregivers of terminally ill patients are women—wives, daughters, sisters, and even daughters-in-law. Since many are widowed, women tend to be able to rely less on family for caregiving assistance and may need more paid assistance. About 20% of terminally ill patients report substantial unmet needs for nursing and personal care. The impact of caregiving on family caregivers is substantial: both bereaved and current caregivers have a higher mortality rate than that of non-caregiving controls.
It is imperative to inquire about unmet needs and to try to ensure that those needs are met either through the family or by paid professional services when possible. Community assistance through houses of worship or other community groups often can be mobilized by telephone calls from the medical team to someone the patient or family identifies. Sources of support specifically for family caregivers should be identified through local sources or nationally through groups such as the National Family Caregivers Association (www.nfcacares.org), the American Cancer Society (www.cancer.org), and the Alzheimer’s Association (www.alz.org).
EXISTENTIAL NEEDS AND THEIR MANAGEMENT
Religion and spirituality are often important to dying patients. Nearly 70% of patients report becoming more religious or spiritual when they became terminally ill, and many find comfort in religious or spiritual practices such as prayer. However, ~20% of terminally ill patients become less religious, frequently feeling cheated or betrayed by becoming terminally ill. For other patients, the need is for existential meaning and purpose that is distinct from, and may even be antithetical to, religion or spirituality. When asked, patients and family caregivers frequently report wanting their professional caregivers to be more attentive to religion and spirituality.
Health care providers are often hesitant about involving themselves in the religious, spiritual, and existential experiences of their patients because it may seem private or not relevant to the current illness. But physicians and other members of the care team should be able at least to detect spiritual and existential needs. Screening questions have been developed for a physician’s spiritual history taking. Spiritual distress can amplify other types of suffering and even masquerade as intractable physical pain, anxiety, or depression. The screening questions in the comprehensive assessment are usually sufficient. Deeper evaluation and intervention are rarely appropriate for the physician unless no other member of a care team is available or suitable. Pastoral care providers may be helpful, whether from the medical institution or from the patient’s own community.
Precisely how religious practices, spirituality, and existential explorations can be facilitated and improve end-of-life care is not well established. What is clear is that for physicians, one main intervention is to inquire about the role and importance of spirituality and religion in a patient’s life. This will help a patient feel heard and help physicians identify specific needs. In one study, only 36% of respondents indicated that a clergy member would be comforting. Nevertheless, the increase in religious and spiritual interest among a substantial fraction of dying patients suggests inquiring of individual patients how this need can be addressed. Some evidence supports specific methods of addressing existential needs in patients, ranging from establishing a supportive group environment for terminal patients to individual treatments emphasizing a patient’s dignity and sources of meaning.